Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism.

Autor:	Masilamani AP; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Schulzki R; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Yuan S; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Haase IV; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Kling E; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Dewes F; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Andrieux G; Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany., Börries M; Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany., Schnell O; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Heiland DH; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany., Schilling O; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, Freiburg, Germany.; Institute of Clinical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Ferrarese R; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany., Carro MS; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2022 Jun 17; Vol. 25 (7), pp. 104625. Date of Electronic Publication: 2022 Jun 17 (Print Publication: 2022).
DOI:	10.1016/j.isci.2022.104625
Abstrakt:	Proteolytic cleavage is an important post-translational mechanism to increase protein variability and functionality. In cancer, this process can be deregulated to shut off tumor-suppressive functions. Here, we report that in glioblastoma (GBM), the tumor suppressor ZBTB18 is targeted for protein cleavage by the intracellular protease calpain. The N-terminal (Nte) ZBTB18 cleaved fragment localizes to the cytoplasm and thus, is unable to exert the gene expression repressive function of the uncleaved protein. Mass spectrometry (MS) analysis indicates that the Nte ZBTB18 short form (SF) interacts with C-terminal (Cte) binding proteins 1 and 2 (CTBP1/2), which appear to be involved in HIF1A signaling activation. In fact, we show that the new ZBTB18 product activates HIF1A-regulated genes, which in turn lead to increased lipid uptake, lipid droplets (LD) accumulation, and enhanced metabolic activity. We propose that calpain-mediated ZBTB18 cleavage represents a new mechanism to counteract ZBTB18 tumor suppression and increase tumor-promoting functions in GBM cells. Competing Interests: The authors declare no competing interests. (© 2022 The Author(s).)
Databáze:	MEDLINE
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